Serine/Threonine Phosphatases in Atrial Fibrillation

Abstract

Serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function. Accordingly, dysfunction of this regulation can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins. Here, we review AF-associated alterations in the phosphorylation of atrial ion channels, calcium-handling and contractile proteins, and their role in AF-pathophysiology. We highlight the mechanisms controlling the phosphorylation of these proteins and focus on the role of altered dephosphorylation via local type-1, type-2A and type-2B phosphatases (PP1, PP2A, and PP2B, also known as calcineurin, respectively). Finally, we discuss the challenges for phosphatase research, potential therapeutic significance of altered phosphatase-mediated protein dephosphorylation in AF, as well as future directions.

Keywords: atrial fibrillation; calcium handling; ion channels; myofilaments; protein phosphatases.

Fig. 1. Schematic overview of the general concepts of AF pathophysiology

AF is induced and maintained by ectopic activity and reentry. Reentry requires an arrhythmogenic substrate and a suitable trigger to initiate it. The trigger usually involves premature beats or rapid ectopic firing. Numerous risk factors including genetics and cardiovascular and non-cardiovascular comorbidities cause alterations in atrial function and structure (remodeling) increasing the likelihood of ectopic activity and reentry. The remodeled substrate include effective refractory period (ERP) changes, conduction slowing and atrial fibrosis, ectopic activity is believed to result from abnormal automaticity, early (EADs) and delayed (DADs) afterdepolarizations and activation of autonomic nervous system (ANS). Increased activity of serine/threonine protein phosphatases, altered local phosphatase targeting and the subsequent alterations in protein phosphorylation are suggested to mediated the effects of atrial remodeling promoting the induction and maintenance of AF by increasing the likelihood of ectopic activity and reentry.

Fig. 2. Schematic overview of protein phosphatase complexes regulating the local phosphorylation of individual ion channels and Ca²⁺-handling proteins

Adapted from Heijman et al. [12].

Fig. 3. Schematic overview of altered protein phosphorylation and phosphatase activity in cAF patients